Many drugs have been developed for cancer therapy. However, an antitumor agent, which selectively exhibits a cell-killing effect only on tumor tissues, has not yet been developed to date. When an antitumor substance is directly administered into a blood vessel, the substance promptly disappears from the blood, and it is distributed even in organs other than the target organ. Thus, a majority of such antitumor substances cannot exhibit a sufficient antitumor activity on cancerous tissues. In addition, these antitumor substances have undesired action on normal tissues (side effect) and cause significant toxicity. Accordingly, the enhancement of the antitumor activity of antitumor substances and reduction in side effects are important subjects for cancer chemotherapy, and it has been strongly desired to develop a Drug Delivery System (DDS) for efficiently accumulating a drug in cancerous tissues and cancer cells.
Liposome is a closed vesicle comprising, as a main ingredient, a biological component-derived phospholipid. The liposome is characterized in that it exhibits low toxicity and low antigenicity when it is administered to a living body. Moreover, it has been shown that the stability in blood and biological distribution of a drug are changed by encapsulating the drug in a liposome, and that as a result, the accessibility of the drug to the target tissues can be improved. Furthermore, it has also been known that the blood vessel walls of new blood vessels often appearing in cancerous tissues have permeability higher than that of the existing blood vessels, and that vesicles such as liposome are likely to accumulate in the cancerous tissues. Accordingly, a liposome medicament is one of DDS, which is highly anticipated to enhance antitumor activity and reduce side effects.
However, when a liposome medicament containing an antitumor substance is used for cancer therapy, an ordinary liposome composition has only an insufficient property of selectively reaching cancerous tissues, and thus, the antitumor effect of the antitumor substance cannot be sufficiently exhibited in many cases. Moreover, such a liposome medicament is also problematic in that side effects appear as a result of distribution of a large amount of liposome in organs other than the target organ. Hence, the aforementioned problems are intended to be solved by two approaches, namely, passive DDS and active DDS.
Passive DDS is a method, which comprises modifying a liposome with a hydrophilic polymer such as polyethylene glycol to impart a high blood retention property to the liposome, so as to allow the liposome to accumulate in tissues with increased blood vessel permeability, such as tumor tissues and inflammatory sites (see Patent Document 1 and Patent Document 2). As a modifier used for modifying a membrane with a hydrophilic polymer, a polyethylene glycol derivative formed by binding a phospholipid, a cholesterol or the like to polyethylene glycol (PEG) is generally used.
Active DDS is a method, which comprises physically or chemically modifying a lipid membrane of liposome with a peptide, protein or antibody having a property of selectively aggregating to cancerous tissues, so as to increase the transitivity of the liposome to the cancerous tissues. As a peptide with affinity for tumor tissues, there is well-known a peptide, which specifically transfers to integrin that is hardly present in normal tissues and is specifically expressed in new blood vessels in tumor and which binds thereto. Representative examples of such a peptide includes peptides comprising an RGD sequence. It has been reported that these peptides selectively bind to integrins αvβ3 and αvβ5, which are expressed in new blood vessels in tumor. However, when a lipid membrane of liposome has been modified with only these peptides, the obtained effects have been insufficient in many cases, although selective transitivity to cancerous tissues and an increased antitumor effect have been observed. Furthermore, in many cases, the types of animal species and cancers, in which antitumor effects have been recognized, have been limited. Although the type of a peptide and the modification level have been changed in various ways, the increased level of the antitumor effect has been restricted. Accordingly, it is considered that there is a high hurdle to jump to develop a drug available in clinical sites. For example, in Patent Document 3, a liposome is modified using a peptide containing 3 to 15 amino acids. In this technique, however, accumulation ability has not been sufficient. In addition, a liposome whose surface has been modified with a sugar chain accumulating in cancer is not sufficient, either, in terms of accumulation ability.
On the other hand, biological polymers, such as gelatin, have been widely used to date as medical materials. With recent advances in genetic engineering, recombinant proteins have been produced by introducing various genes in Escherichia coli or yeast. By this genetic engineering, various types of recombinant collagen-like proteins have been synthesized (Patent Documents 4 and 5). When compared with natural gelatin, these recombinant collagen-like proteins have excellent non-infectivity and uniformity. Moreover, the recombinant collagen-like proteins are also advantageous in that, since their sequences have been determined, the strength and degradability thereof can be designed precisely. Patent Document 6 discloses that a sequence which contains many RGD sequences is useful as a drug delivery agent. However, this document does not suggest that the combination of such a sequence with a liposome is useful.